Diagnostic and prognostic assay for a condition or event of the vascular system

ABSTRACT

The present disclosure relates generally to the field of diagnostic and prognostic assays for a condition or event of a vascular system such as the cerebrovascular system. An assay is taught herein for monitoring progression of a condition or event of a vascular system such as the cerebrovascular system as well as determining the state or stage of the condition or event. The assay of the present disclosure is also useful in the stratification of a subject based on the stage or development of the condition or event.

FILING DATA

This application is associated with and claims priority from Australian Provisional Patent Application No. 2011900274, filed on 28 Jan. 2011, entitled “Diagnostic and prognostic assay”, the entire contents of which, are incorporated herein by reference.

FIELD

The present disclosure relates generally to the field of diagnostic and prognostic assays for a condition or event of a vascular system such as the cerebrovascular system. An assay is taught herein for monitoring progression of a condition or event of a vascular system such as the cerebrovascular system as well as determining the state or stage of the condition or event. The assay of the present disclosure is also useful in the stratification of a subject based on the stage or development of the condition or event.

BACKGROUND

Bibliographic details of the publications referred to by author in this specification are collected alphabetically at the end of the description.

Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in any country.

Adverse conditions and events of vascular systems represent a major course of morbidity and mortality in many populations. This is particularly the case for the cerebrovascular system. One such condition of a vascular system such as the cerebrovascular system is stroke which is the third most common cause of death amongst populations within most Western countries (Strong et al. (2007) Lancet Neurol 6:182-187,). It also represents a significant cause of disability ranging from minor to extremely disabling. Approximately 85% of strokes are of ischemic origin due to vessel occlusion and approximately 15% of strokes are due to vessel rupture and intracranial hemorrhage (ICH). To put the significance of stroke into perspective, the World Heath Organisation estimates that globally 20 million people suffer a stroke each year of which approximately 5.1 million die. In addition, over 200 million people suffer “silent strokes” which nevertheless contribute to some form of vascular dementia.

Approximately 20% of patients die within the first month of having a stroke with 37% dying in the first year. Approximately 24% to 50% of survivors exhibit some form of dementia or cognitive decline within a year of the stroke, requiring a certain amount of dependency on others.

Quite apart from the personal effects on the quality of life on the survivors or on members of their families, the high incidence of stroke places an enormous burden on already struggling private and public health care systems.

The treatment of stroke is generally divided into four categories: intravenous thrombolysis, oral aspirin, management in a dedicated stroke unit (i.e. patient care) and hemicraniectomy, when malignant brain oedema requires surgical decompression (Donnan et al., (2008) Lancet 371:1612-1523).

The most specific and efficacious of these treatments is thrombolysis with tissue plasminogen activator (tPA) if given within 4.5 hours of ischemic stroke onset (Hacke et al. (2008) N. Engl. J. Med 359:1317-1329). Results of tPA treatment range from a benefit of one patient per 3.6 patients treated within 90 minutes of stroke to one patient benefited per 19.3 patients 270-360 minutes after stroke. However, generally, only about 1% of stroke victims receive thrombolytic treatment due to the need to establish whether the stroke is of ischemic or hemorrhagic in nature, the absence of imaging resources in many hospitals or point of care facilities and the presence of high blood pressure which is contraindicated for patients receiving thrombolytic therapy (Hacke et al. (2004) Lancet 363:768-774; Lees et al. (2010) Lancet 375:1695-1703).

It is apparent that restoration of blood flow promptly after onset of ischemic stroke has the potential to assist a much larger group than currently are treated using the “clock” time period of from 0 to 4.5 hours from onset.

There is a need, therefore, to be able to stratify a patient to establish a time line from a biological and temporal perspective in the evolution of stroke and other thromboembolic and non-thromboembolic conditions and events.

SUMMARY

Throughout this specification, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element or integer or method step or group of elements or integers or method steps but not the exclusion of any other element or integer or method step or group of elements or integers or method steps.

As used in the subject specification, the singular forms “a”, “an” and “the” include plural aspects unless the context clearly dictates otherwise. Thus, for example, reference to “a biomarker” includes a single biomarker, as well as 2 or more biomarkers; reference to “an event” includes a single event or two or more events; reference to “the disclosure” includes single and multiple aspects taught by the disclosure. All aspects taught herein are encompassed by the term “invention”. All aspects of the invention are enabled within the width of the claims.

The use of numerical values in the various ranges specified in this specification, unless expressly indicated otherwise, are stated as approximations as though the minimum and maximum values within the stated ranges were both preceded by the word “about”. In this manner, slight variations above and below the stated ranges can be used to achieve substantially the same results as values within the ranges. Also, the disclosure of these ranges is intended as a continuous range including every value between the minimum and maximum values. In addition, the present disclosure extends to ratios of the levels of 2 or more biomarkers providing a numerical value associated with progression of a condition or event of a vascular system such as the cerebrovascular system.

A method is taught herein for monitoring progression of a condition or event of a vascular system such as the cerebrovascular system in a subject. The method comprises determining the levels or ratios of levels of 2 or more biomarkers and comparing these levels or ratios to a control. The control comprises pre-determined levels or ratios from subjects with a known status with respect to the condition or event. The biomarkers are selected on the basis that their levels dynamically alter during evolution of the condition or event in a relatively statistically reproducible manner within a pre-determined period. Hence, the biomarker is selected on the basis that its level increases or decreases over a time period. Consequently, a physiological time period is thereby established wherein the levels or ratios of levels of the biomarkers at least correlate to the levels or ratios of levels observed in a pre-determined “clock” time period following onset of the condition or event. The biomarkers are used to define a physiological time period following onset of the condition or event rather than clock time defining this period. It is proposed that the physiological time period is wider than the corresponding clock time period following onset of the acute condition or event. This has the consequence of re-defining various therapeutic windows. This has relevance to both acute conditions and events as well as chronic conditions and events.

The acute condition or event of a vascular system such as the cerebrovascular system may be ischemic or hemorrhagic in nature or origin. Examples of ischemic conditions and events include ischemic stroke and ischemic myocardial infarction. Examples of a hemorrhagic condition or event is hemorrhagic stroke. The biomarkers are also proposed be useful in distinguishing between conditions or events such as differentiating between ischemic stroke and hemorrhagic stroke. A chronic condition or event includes vascular dementia which may develop over time.

In an embodiment, the condition or event is ischemic stroke including its various manifestations such as pre-stroke, transient ischemic attack and acute ischemic stroke as well as other related thromboembolic events. Generally, such conditions and events have the potential to lead to some form of adverse neurological condition.

Useful biomarkers contemplated herein are those listed in Table 1 by Affymetrix gene identifier (ID) number. A particular set of biomarkers is provided in Table 2. The genes are listed by p-value of the F-statistic in decreasing order of significance across all time points. In relation to ischemic stroke, the levels or ratios of levels of 2 or more of the biomarkers correlate to levels within a pre-determined time period after onset. In an embodiment, the pre-determined time period is the therapeutic window for thrombolytic intervention, generally from about 0 hours to 4.5 hours or a sub-fraction thereof after onset. In accordance with the present disclosure, although on a “clock” basis, 4.5 hours may represent the cutoff point for thrombolytic treatment, the “physiological clock” is proposed herein to extend the 4.5 hours cutoff point to greater than 4.5 hours such as between 4.5 hours and 10 hours. Hence, more patients can receive thrombolytic treatment. In another embodiment, the condition may be chronic requiring ongoing treatment over months or years. In yet a further embodiment, the chronic condition may reach a point requiring medical intervention. It is proposed herein that the biomarker expression profile is used to define when a chronic condition or potential chronic condition enters a therapeutic window.

Of the biomarkers listed in Table 1, all biomarkers may be measured or from about 2 to about 20 biomarkers may be measured or from about 2 to about 15 such as 12 biomarkers may be measured. By “measured” means determining levels, concentrations or velocities of a biomarker. The value may be the actual level or a ratio of levels. The term “biomarker” extends to both a gene and a gene product such as a protein or mRNA transcript. In a most particular embodiment, the 2 or more biomarkers are selected from Table 2.

In an embodiment, the subject is a human. Hence, the assay of the present disclosure permits stratification of a subject on the basis of extent of progression of the condition or event based on physiological markers rather than on “clock time”. In an embodiment, the stratification enables identification of a therapeutic window for thrombolytic intervention. This window is defined as the levels or ratios of levels of biomarkers which equate to the levels or ratios at from about 0 hours to about 4.5 hours (or other pre-determined time period) after onset of the condition or event. It is proposed herein that the “physiological clock time” is longer than the 4.5 hour clock time recommended for thrombolytic treatment. For chronic conditions or events, the profile of biomarker expression may define when therapy is required. Onset of the condition may have been years earlier. Vascular dementia is one example.

A method is enabled herein for treating a subject who has or is suspected of having suffered a condition or event of a vascular system such as the cerebrovascular system. The method comprises determining levels or ratios of biomarkers which equate to the levels or ratios at a pre-determined time period. In the case of ischemic stroke, the pre-determined time period is 0 to 4.5 hours. This is the therapeutic window for thrombolytic intervention in the case of an ischemic condition or event. If the subject has biomarker levels or ratios instructive to this therapeutic window, then a thrombolytic agent is administered. In addition or alternatively, the treatment may involve oral aspirin administration, patient care and/or hemicraniectomy. In an example, the condition or event is ischemic stroke or ischemic myocardial infarction. The biomarkers include 2 or more selected from the list in Table 1 and such as 2 or more biomarkers selected from the list in Table 2. In another embodiment, the therapeutic window is defined when biomarker expression reaches a particular profile. This may be a time or age-based period or it may depend on the severity of symptoms. Hence, treatment is initiated when the expression profile of the biomarkers equates to levels corresponding to a set of symptoms.

The present disclosure further teaches the use of 2 or more biomarkers, the levels of which dynamically alter during evolution of an acute condition or event of a vascular system such as the cerebrovascular system in a subject, in the manufacture of a diagnostic assay to determine the extent of progression of the condition or event. A biomarker which remains stable over a time period may also be selected as a control or to use in a ratio determination with a biomarker with increases or decreases over time. Furthermore, the present disclosure contemplates the use of a multivariate statistical model based on determining the levels or ratios of levels of 2 or more biomarkers to establish an expression profile of the biomarkers.

Kits and web-based assays are also enabled herein. A web-based assay is useful for point of care facilities for the rapid reporting of diagnostic information.

Tables 1 and 2 list biomarkers useful in the practice of the present assay by Affymetrix gene identifier (ID) number (Affymetrix gene identifier). Information on the genes can be obtained from the Affymetrix website [NetAffx (Trademark)] which can be accessed at http://www.affymetrix.com/analysis/index.affx. Where available, an ENSEMBL identifier is also provided which can be accessed through the ENSEMBL rat genome website at http://www.ensembl.org/Rattus_norvegicus. Where an ENSEMBL number is not available, the term “NA” is used. Although genes are listed in Tables 1 and 2, the term “biomarker” extends to both genes and gene products. A gene product may be a protein or mRNA transcript. The genes are listed by increasing p-value of the F-statistic.

TABLE 1 Biomarkers affymetrix gene ID p-value for F-statistic ENSEMBL annotations 10722208 1.21E−26 ENSRNOG00000014227 10810144 1.03E−24 ENSRNOG00000023272 10940615 5.06E−24 NA 10736312 6.12E−24 ENSRNOG00000011023 10826956 2.33E−23 NA 10763768 5.25E−23 ENSRNOG00000004441 10748273 5.43E−23 ENSRNOG00000011917 10922816 1.22E−22 ENSRNOG00000014378 10783880 1.29E−22 ENSRNOG00000020136 10707142 1.51E−22 ENSRNOG00000013103 10826703 4.36E−22 ENSRNOG00000010875 10909411 4.42E−22 ENSRNOG00000006663 10828832 4.58E−22 ENSRNOG00000001869 10705065 5.11E−22 ENSRNOG00000020125 10721261 7.52E−22 ENSRNOG00000037331 10864433 8.59E−22 ENSRNOG00000010898 10732941 8.98E−22 ENSRNOG00000028845 10728883 9.47E−22 ENSRNOG00000020945 10893918 2.16E−21 ENSRNOG00000013987 10892472 2.56E−21 ENSRNOG00000037529 10823363 2.80E−21 ENSRNOG00000029756 10826969 3.91E−21 NA 10769765 4.07E−21 ENSRNOG00000003136 10735331 4.83E−21 ENSRNOG00000004078 10824305 7.07E−21 ENSRNOG00000019737 10922492 8.25E−21 ENSRNOG00000015382 10826943 8.70E−21 NA 10810923 9.55E−21 ENSRNOG00000014964 10836588 1.62E−20 ENSRNOG00000006773 10880404 1.69E−20 ENSRNOG00000013231 10812292 1.88E−20 NA 10849279 1.89E−20 ENSRNOG00000018204 10933912 2.07E−20 ENSRNOG00000038299 10751437 2.22E−20 ENSRNOG00000038831 10766428 2.32E−20 NA 10730131 2.34E−20 ENSRNOG00000013967 10703764 2.40E−20 ENSRNOG00000038774 10775519 2.50E−20 ENSRNOG00000002159 10926252 2.70E−20 NA 10808959 2.90E−20 ENSRNOG00000010744 10894369 3.97E−20 ENSRNOG00000039204 10924230 4.54E−20 NA 10725684 4.62E−20 ENSRNOG00000018311 10792028 4.74E−20 ENSRNOG00000011474 10868627 4.75E−20 ENSRNOG00000014838 10749372 5.06E−20 ENSRNOG00000002946 10808377 5.07E−20 ENSRNOG00000016752 10832602 5.51E−20 ENSRNOG00000001304 10927195 6.59E−20 ENSRNOG00000011771 10800546 9.52E−20 ENSRNOG00000015113 10831940 1.22E−19 ENSRNOG00000022523 10828827 1.33E−19 ENSRNOG00000000521 10751434 1.44E−19 ENSRNOG00000028918 10933431 1.46E−19 ENSRNOG00000003705 10747506 1.48E−19 ENSRNOG00000019742 10862082 1.58E−19 ENSRNOG00000010957 10716939 1.72E−19 ENSRNOG00000011411 10817074 1.79E−19 ENSRNOG00000021798 10738071 2.04E−19 ENSRNOG00000009643 10703757 2.41E−19 ENSRNOG00000038775 10755013 2.74E−19 ENSRNOG00000001928 10703776 2.80E−19 ENSRNOG00000014812 10740843 3.29E−19 ENSRNOG00000029621 10865948 3.61E−19 ENSRNOG00000007310 10762051 3.88E−19 ENSRNOG00000001270 10775398 3.95E−19 ENSRNOG00000002186 10759999 4.05E−19 ENSRNOG00000000907 10925158 4.34E−19 NA 10845708 4.40E−19 ENSRNOG00000006227 10750524 4.50E−19 ENSRNOG00000001963 10860597 4.73E−19 ENSRNOG00000008602 10840448 4.93E−19 ENSRNOG00000010131 10715301 5.42E−19 ENSRNOG00000014551 10940647 5.49E−19 NA 10773961 5.66E−19 ENSRNOG00000010298 10794116 6.53E−19 ENSRNOG00000026235 10841693 7.26E−19 ENSRNOG00000014532 10931017 8.58E−19 NA 10750277 8.65E−19 ENSRNOG00000002010 10774171 9.28E−19 ENSRNOG00000004972 10883903 9.50E−19 ENSRNOG00000023272 10814331 9.52E−19 ENSRNOG00000011441 10778028 9.63E−19 ENSRNOG00000004280 10910619 9.88E−19 ENSRNOG00000012868 10851560 9.96E−19 ENSRNOG00000028779 10926277 1.09E−18 ENSRNOG00000022859 10873355 1.11E−18 ENSRNOG00000017401 10754592 1.45E−18 ENSRNOG00000001793 10906373 1.47E−18 ENSRNOG00000026128 10901409 1.49E−18 ENSRNOG00000008885 10762254 1.53E−18 ENSRNOG00000033220 10846286 1.58E−18 ENSRNOG00000001548 10901413 1.59E−18 ENSRNOG00000009088 10755544 1.61E−18 ENSRNOG00000001907 10931034 1.72E−18 NA 10932037 1.80E−18 ENSRNOG00000009746 10783933 1.81E−18 ENSRNOG00000020401 10839320 1.93E−18 ENSRNOG00000000172 10812354 1.98E−18 ENSRNOG00000032789 10779006 2.16E−18 ENSRNOG00000013112 10897428 2.21E−18 ENSRNOG00000000187 10923470 2.75E−18 ENSRNOG00000011771 10750282 2.91E−18 ENSRNOG00000027076 10809204 2.98E−18 ENSRNOG00000014896 10753959 3.24E−18 ENSRNOG00000030246 10828778 3.29E−18 ENSRNOG00000000515 10851581 3.39E−18 ENSRNOG00000030539 10751871 3.46E−18 ENSRNOG00000001931 10891352 3.50E−18 ENSRNOG00000012210 10940686 3.80E−18 NA 10773148 3.83E−18 ENSRNOG00000005261 10796440 4.45E−18 ENSRNOG00000017328 10863430 4.57E−18 ENSRNOG00000006116 10756178 4.60E−18 ENSRNOG00000001005 10845814 4.60E−18 ENSRNOG00000005727 10794866 4.68E−18 ENSRNOG00000016581 10718351 5.16E−18 ENSRNOG00000011174 10726550 5.37E−18 ENSRNOG00000017897 10911315 5.54E−18 ENSRNOG00000011886 10709860 6.31E−18 ENSRNOG00000009910 10940619 6.40E−18 NA 10940620 7.11E−18 NA 10764722 7.37E−18 ENSRNOG00000028016 10924245 7.72E−18 ENSRNOG00000014269 10916016 8.48E−18 ENSRNOG00000009850 10907924 9.10E−18 ENSRNOG00000040208 10826691 9.73E−18 ENSRNOG00000024492 10774383 9.87E−18 ENSRNOG00000007125 10871957 1.04E−17 ENSRNOG00000008759 10912218 1.06E−17 ENSRNOG00000008048 10820223 1.12E−17 ENSRNOG00000033134 10703508 1.13E−17 ENSRNOG00000030444 10722992 1.19E−17 ENSRNOG00000014610 10900735 1.26E−17 ENSRNOG00000033564 10825443 1.28E−17 ENSRNOG00000037190 10754363 1.32E−17 ENSRNOG00000032728 10898315 1.33E−17 ENSRNOG00000014137 10922882 1.38E−17 ENSRNOG00000015062 10801821 1.45E−17 ENSRNOG00000013774 10940628 1.51E−17 NA 10852636 1.52E−17 NA 10733849 1.53E−17 ENSRNOG00000002820 10920860 1.54E−17 ENSRNOG00000013634 10788627 1.83E−17 ENSRNOG00000010392 10766998 1.83E−17 ENSRNOG00000030444 10782668 2.16E−17 ENSRNOG00000008024 10746293 2.29E−17 ENSRNOG00000002948 10821383 2.38E−17 ENSRNOG00000010971 10721268 2.42E−17 ENSRNOG00000022640 10852200 2.55E−17 ENSRNOG00000004529 10858581 2.65E−17 ENSRNOG00000027655 10854737 2.79E−17 NA 10703751 3.79E−17 ENSRNOG00000038776 10905689 3.79E−17 ENSRNOG00000007664 10880960 3.85E−17 ENSRNOG00000006855 10772770 4.20E−17 NA 10712171 4.25E−17 ENSRNOG00000004273 10739913 4.91E−17 NA 10858390 4.94E−17 ENSRNOG00000013547 10711260 5.39E−17 ENSRNOG00000022099 10834502 5.60E−17 ENSRNOG00000009239 10866850 5.70E−17 ENSRNOG00000009338 10717620 5.70E−17 ENSRNOG00000018960 10826954 5.79E−17 NA 10767716 6.11E−17 ENSRNOG00000028250 10940529 6.41E−17 NA 10795646 6.48E−17 ENSRNOG00000018972 10858648 6.98E−17 ENSRNOG00000011718 10739353 7.74E−17 ENSRNOG00000004720 10910641 8.30E−17 ENSRNOG00000013013 10709880 8.69E−17 ENSRNOG00000018262 10922428 9.01E−17 ENSRNOG00000013415 10723866 9.07E−17 ENSRNOG00000016573 10894616 9.88E−17 ENSRNOG00000039003 10771012 1.04E−16 ENSRNOG00000023533 10747330 1.04E−16 ENSRNOG00000015380 10901962 1.10E−16 ENSRNOG00000007970 10722317 1.12E−16 ENSRNOG00000012690 10893258 1.15E−16 ENSRNOG00000007650 10703666 1.21E−16 ENSRNOG00000011236 10718934 1.22E−16 ENSRNOG00000027855 10733982 1.22E−16 ENSRNOG00000003170 10785590 1.24E−16 ENSRNOG00000009145 10772768 1.24E−16 ENSRNOG00000002161 10751431 1.30E−16 ENSRNOG00000033929 10798420 1.37E−16 ENSRNOG00000003094 10831077 1.39E−16 ENSRNOG00000000827 10903971 1.41E−16 ENSRNOG00000029292 10776888 1.43E−16 ENSRNOG00000026504 10865381 1.49E−16 ENSRNOG00000010203 10849125 1.62E−16 ENSRNOG00000022868 10814480 1.68E−16 ENSRNOG00000011119 10765195 1.72E−16 ENSRNOG00000002794 10826967 1.75E−16 NA 10816144 1.80E−16 ENSRNOG00000009465 10756161 1.83E−16 ENSRNOG00000040128 10751091 1.84E−16 ENSRNOG00000002141 10864840 1.95E−16 ENSRNOG00000011614 10870046 2.00E−16 ENSRNOG00000007551 10858599 2.02E−16 ENSRNOG00000010181 10818326 2.02E−16 ENSRNOG00000031814 10779002 2.07E−16 ENSRNOG00000033011 10869487 2.18E−16 ENSRNOG00000008712 10938219 2.19E−16 ENSRNOG00000034116 10704665 2.28E−16 ENSRNOG00000013395 10826682 2.30E−16 ENSRNOG00000022636 10769735 2.30E−16 ENSRNOG00000024632 10929319 2.41E−16 ENSRNOG00000018972 10764079 2.77E−16 ENSRNOG00000003336 10754995 2.82E−16 ENSRNOG00000001930 10744687 3.01E−16 ENSRNOG00000014870 10828344 3.05E−16 ENSRNOG00000032844 10794225 3.16E−16 ENSRNOG00000011668 10801884 3.31E−16 ENSRNOG00000015971 10820282 3.64E−16 ENSRNOG00000029212 10875680 3.74E−16 ENSRNOG00000006298 10860327 3.75E−16 ENSRNOG00000006526 10759604 4.05E−16 ENSRNOG00000028259 10863726 4.55E−16 ENSRNOG00000017720 10752262 4.64E−16 ENSRNOG00000030506 10736486 5.10E−16 ENSRNOG00000003873 10829116 5.12E−16 ENSRNOG00000001169 10837621 5.18E−16 ENSRNOG00000026128 10826958 5.36E−16 ENSRNOG00000032247 10700478 5.45E−16 NA 10731922 5.60E−16 ENSRNOG00000008134 10730636 5.60E−16 ENSRNOG00000020325 10817370 5.75E−16 ENSRNOG00000021131 10864512 5.86E−16 ENSRNOG00000005954 10796149 5.96E−16 ENSRNOG00000018911 10940618 5.97E−16 ENSRNOG00000042912 10799461 6.10E−16 ENSRNOG00000029235 10720790 6.45E−16 ENSRNOG00000021021 10788427 6.55E−16 ENSRNOG00000012779 10758351 6.72E−16 ENSRNOG00000026653 10872935 6.73E−16 ENSRNOG00000009260 10903977 6.76E−16 ENSRNOG00000028190 10901910 7.02E−16 ENSRNOG00000005266 10701934 7.15E−16 ENSRNOG00000012259 10857950 7.46E−16 ENSRNOG00000007486 10818594 7.68E−16 ENSRNOG00000015029 10716896 7.74E−16 ENSRNOG00000015473 10909761 7.78E−16 ENSRNOG00000018778 10909590 7.88E−16 ENSRNOG00000016085 10782511 8.04E−16 ENSRNOG00000005883 10878674 8.32E−16 ENSRNOG00000033593 10834719 8.56E−16 ENSRNOG00000009446 10746968 9.04E−16 ENSRNOG00000036862 10929211 9.26E−16 ENSRNOG00000013213 10714273 9.45E−16 ENSRNOG00000025644 10829993 1.01E−15 ENSRNOG00000000569 10854832 1.06E−15 ENSRNOG00000026177 10842239 1.07E−15 ENSRNOG00000017539 10864404 1.12E−15 ENSRNOG00000009184 10840890 1.14E−15 ENSRNOG00000021750 10936365 1.15E−15 ENSRNOG00000013170 10816278 1.16E−15 ENSRNOG00000034230 10733056 1.19E−15 ENSRNOG00000002470 10754983 1.23E−15 ENSRNOG00000013170 10744545 1.24E−15 ENSRNOG00000037409 10813361 1.30E−15 ENSRNOG00000028930 10768742 1.36E−15 ENSRNOG00000026952 10788374 1.45E−15 ENSRNOG00000010748 10763758 1.52E−15 ENSRNOG00000004405 10895589 1.56E−15 ENSRNOG00000034134 10706346 1.62E−15 ENSRNOG00000023411 10924803 1.64E−15 ENSRNOG00000017256 10914799 1.67E−15 ENSRNOG00000005731 10716303 1.68E−15 ENSRNOG00000017225 10889965 1.77E−15 ENSRNOG00000006828 10842707 1.84E−15 ENSRNOG00000024702 10848450 1.84E−15 ENSRNOG00000008229 10770778 1.86E−15 ENSRNOG00000005565 10819644 1.93E−15 ENSRNOG00000014613 10725953 1.98E−15 ENSRNOG00000036711 10824695 2.04E−15 ENSRNOG00000011483 10888610 2.17E−15 ENSRNOG00000039902 10794242 2.31E−15 ENSRNOG00000013679 10905335 2.39E−15 ENSRNOG00000008401 10802013 2.40E−15 ENSRNOG00000018735 10854847 2.59E−15 ENSRNOG00000026177 10927562 2.81E−15 ENSRNOG00000018830 10728240 2.85E−15 ENSRNOG00000021125 10886036 2.86E−15 ENSRNOG00000008224 10716746 3.04E−15 NA 10705034 3.30E−15 ENSRNOG00000020090 10750460 3.36E−15 ENSRNOG00000001647 10766726 3.39E−15 ENSRNOG00000003915 10811956 3.41E−15 ENSRNOG00000019791 10864848 3.51E−15 ENSRNOG00000012972 10878617 3.55E−15 ENSRNOG00000010859 10807140 3.68E−15 ENSRNOG00000014668 10709135 3.84E−15 ENSRNOG00000019319 10922826 3.90E−15 ENSRNOG00000014504 10708521 3.94E−15 ENSRNOG00000016496 10801308 4.25E−15 ENSRNOG00000013920 10818920 4.33E−15 ENSRNOG00000011589 10735182 4.36E−15 ENSRNOG00000018715 10766760 4.36E−15 ENSRNOG00000004402 10759717 4.78E−15 ENSRNOG00000000973 10796445 4.80E−15 ENSRNOG00000018087 10807452 4.93E−15 ENSRNOG00000018618 10826672 4.98E−15 ENSRNOG00000022636 10700829 5.19E−15 NA 10794084 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2.37E−07 ENSRNOG00000033747 10783510 2.39E−07 ENSRNOG00000039429 10865329 2.39E−07 ENSRNOG00000015411 10813191 2.41E−07 ENSRNOG00000017581 10712853 2.41E−07 ENSRNOG00000018752 10776915 2.44E−07 ENSRNOG00000002180 10716189 2.44E−07 ENSRNOG00000013993 10931537 2.45E−07 NA 10702768 2.46E−07 ENSRNOG00000016728 10940539 2.46E−07 NA 10903545 2.48E−07 ENSRNOG00000027690 10729350 2.50E−07 ENSRNOG00000030572 10742533 2.50E−07 ENSRNOG00000004956 10870316 2.50E−07 ENSRNOG00000010833 10923799 2.53E−07 ENSRNOG00000010283 10902564 2.53E−07 ENSRNOG00000006304 10826474 2.54E−07 ENSRNOG00000011929 10859296 2.55E−07 ENSRNOG00000008676 10715721 2.57E−07 ENSRNOG00000018704 10803394 2.62E−07 ENSRNOG00000015895 10819562 2.65E−07 ENSRNOG00000009205 10869050 2.66E−07 ENSRNOG00000022325 10787828 2.66E−07 ENSRNOG00000029441 10854957 2.66E−07 NA 10748200 2.68E−07 ENSRNOG00000025448 10899619 2.68E−07 ENSRNOG00000025891 10783805 2.69E−07 ENSRNOG00000019246 10771406 2.69E−07 ENSRNOG00000002217 10804132 2.71E−07 ENSRNOG00000014096 10826771 2.72E−07 ENSRNOG00000009877 10783501 2.73E−07 ENSRNOG00000042987 10825276 2.74E−07 ENSRNOG00000018220 10866507 2.74E−07 ENSRNOG00000005670 10855850 2.75E−07 ENSRNOG00000006858 10755846 2.77E−07 ENSRNOG00000001813 10726691 2.83E−07 ENSRNOG00000015593 10855405 2.84E−07 ENSRNOG00000008416 10876688 2.87E−07 ENSRNOG00000008618 10877916 2.88E−07 ENSRNOG00000007663 10703723 2.92E−07 ENSRNOG00000012179 10805540 2.92E−07 ENSRNOG00000015591 10824984 2.93E−07 ENSRNOG00000021120 10821194 2.96E−07 ENSRNOG00000009944 10782065 2.98E−07 ENSRNOG00000010989 10884961 3.01E−07 ENSRNOG00000004791 10939866 3.01E−07 ENSRNOG00000000869 10845070 3.02E−07 ENSRNOG00000039025 10826502 3.03E−07 ENSRNOG00000013798 10856166 3.03E−07 ENSRNOG00000034848 10799383 3.07E−07 ENSRNOG00000018091 10850668 3.07E−07 ENSRNOG00000036934 10923294 3.08E−07 ENSRNOG00000011677 10750848 3.09E−07 ENSRNOG00000031163 10802375 3.11E−07 ENSRNOG00000018770 10846293 3.11E−07 ENSRNOG00000024821 10769138 3.14E−07 ENSRNOG00000002736 10923996 3.16E−07 NA 10786454 3.17E−07 ENSRNOG00000016015 10700151 3.19E−07 NA 10810341 3.20E−07 ENSRNOG00000003496 10877907 3.20E−07 ENSRNOG00000007060 10872929 3.24E−07 ENSRNOG00000007992 10790811 3.25E−07 ENSRNOG00000023370 10740734 3.28E−07 ENSRNOG00000007117 10700759 3.28E−07 NA 10899579 3.29E−07 ENSRNOG00000016100 10883540 3.31E−07 ENSRNOG00000006865 10753024 3.31E−07 ENSRNOG00000002080 10867461 3.33E−07 ENSRNOG00000008180 10902868 3.34E−07 ENSRNOG00000007839 10765040 3.36E−07 ENSRNOG00000035336 10820362 3.41E−07 ENSRNOG00000013673 10871813 3.41E−07 ENSRNOG00000007629 10797863 3.42E−07 ENSRNOG00000014460 10700964 3.46E−07 NA 10708589 3.49E−07 NA 10823184 3.50E−07 ENSRNOG00000013434 10854494 3.50E−07 ENSRNOG00000010852 10850530 3.51E−07 ENSRNOG00000024799 10867944 3.51E−07 ENSRNOG00000007506 10717295 3.55E−07 ENSRNOG00000016219 10784074 3.56E−07 ENSRNOG00000022597 10800993 3.56E−07 ENSRNOG00000018775 10754000 3.60E−07 ENSRNOG00000039048 10701243 3.60E−07 NA 10789534 3.66E−07 ENSRNOG00000017085 10857385 3.70E−07 ENSRNOG00000010536 10848279 3.75E−07 ENSRNOG00000029847 10805375 3.75E−07 ENSRNOG00000016208 10900511 3.75E−07 ENSRNOG00000033262 10784679 3.81E−07 ENSRNOG00000009625 10906592 3.81E−07 ENSRNOG00000005291 10717014 3.81E−07 ENSRNOG00000011409 10754410 3.81E−07 ENSRNOG00000000399 10834406 3.85E−07 ENSRNOG00000004497 10700626 3.85E−07 ENSRNOG00000018091 10897952 3.87E−07 ENSRNOG00000024743 10803799 3.88E−07 ENSRNOG00000024241 10925060 3.99E−07 ENSRNOG00000017020 10789806 4.01E−07 ENSRNOG00000028380 10725819 4.02E−07 ENSRNOG00000023539 10862929 4.02E−07 ENSRNOG00000038346 10766674 4.02E−07 ENSRNOG00000003407 10756767 4.06E−07 ENSRNOG00000001099 10923857 4.09E−07 ENSRNOG00000024186 10704499 4.10E−07 ENSRNOG00000015865 10742674 4.13E−07 ENSRNOG00000042449 10700541 4.14E−07 NA 10771655 4.17E−07 ENSRNOG00000022256 10722315 4.18E−07 ENSRNOG00000034992 10910222 4.18E−07 ENSRNOG00000016905 10785602 4.20E−07 ENSRNOG00000009431 10894540 4.23E−07 ENSRNOG00000006978 10849765 4.26E−07 ENSRNOG00000016965 10904018 4.27E−07 ENSRNOG00000005145 10776976 4.34E−07 ENSRNOG00000017907 10847538 4.34E−07 ENSRNOG00000007732 10878221 4.35E−07 ENSRNOG00000008298 10887669 4.38E−07 ENSRNOG00000004268 10720437 4.40E−07 ENSRNOG00000020576 10869288 4.41E−07 ENSRNOG00000017132 10821340 4.42E−07 ENSRNOG00000010125 10817183 4.46E−07 ENSRNOG00000010105 10855135 4.47E−07 ENSRNOG00000025301 10729094 4.47E−07 ENSRNOG00000035384 10739984 4.48E−07 ENSRNOG00000029658 10750795 4.55E−07 ENSRNOG00000039567 10846631 4.57E−07 ENSRNOG00000012603 10730867 4.58E−07 NA 10809581 4.64E−07 ENSRNOG00000012153 10855576 4.64E−07 ENSRNOG00000008393 10792354 4.66E−07 ENSRNOG00000018241 10744134 4.71E−07 ENSRNOG00000030628 10875880 4.71E−07 ENSRNOG00000008314 10783763 4.72E−07 ENSRNOG00000025619 10929572 4.74E−07 ENSRNOG00000008664 10747439 4.74E−07 ENSRNOG00000018364 10774310 4.74E−07 ENSRNOG00000043210 10917727 4.77E−07 ENSRNOG00000018577 10765542 4.77E−07 ENSRNOG00000003551 10700290 4.78E−07 NA 10933298 4.83E−07 ENSRNOG00000004016 10707961 4.89E−07 ENSRNOG00000010964 10700897 4.90E−07 NA 10815795 4.95E−07 NA 10813236 4.96E−07 ENSRNOG00000015849

TABLE 2 Particular Biomarkers affymetrix gene ID p-value for F-statistic ENSEMBL annotations 10722208 1.21E−26 ENSRNOG00000014227 10940615 5.06E−24 NA 10763768 5.25E−23 ENSRNOG00000004441 10748273 5.43E−23 ENSRNOG00000011917 10922816 1.22E−22 ENSRNOG00000014378 10707142 1.51E−22 ENSRNOG00000013103 10828832 4.58E−22 ENSRNOG00000001869 10721261 7.52E−22 ENSRNOG00000037331 10769765 4.07E−21 ENSRNOG00000003136 10849279 1.89E−20 ENSRNOG00000018204 10775519 2.50E−20 ENSRNOG00000002159 10926252 2.70E−20 NA 10831940 1.22E−19 ENSRNOG00000022523 10751434 1.44E−19 ENSRNOG00000028918 10750524 4.50E−19 ENSRNOG00000001963 10718351 5.16E−18 ENSRNOG00000011174 10911315 5.54E−18 ENSRNOG00000011886 10924245 7.72E−18 ENSRNOG00000014269 10774383 9.87E−18 ENSRNOG00000007125 10754363 1.32E−17 ENSRNOG00000032728 10703666 1.21E−16 ENSRNOG00000011236 10782511 8.04E−16 ENSRNOG00000005883 10854847 2.59E−15 ENSRNOG00000026177 10782493 3.48E−14 ENSRNOG00000005883 10706308 7.84E−14 ENSRNOG00000037339

Where a gene is identified as a “rat gene”, the present disclosure extends to a mammalian homolog thereof and in particular a human homolog. The human homolog may be referred to by a different name.

A list of proteins encoded by genes defined by Affymetrix ID number is provided in Table 3.

TABLE 3 Proteins encoded by genes defined by Affymetrix ID number Affymetrix ID Number Protein 10703666 Pirb, paired-Ig-like receptor B 10706308 Siglec10, sialic acid binding Ig-like lectin 10 10707142 Ldhc, lactate dehydrogenase C 10718351 Fpr1, formyl peptide receptor 1 10721261 LOC687856, similar to myeloid cell surface antigen CD33 precursor 10722208 Mrga10, nuclear receptor Mrga10 RF-amide G protein coupled receptor 10748273 Cd79b, CD79B antigen 10750524 Mx2, myxovirus (influenza virus) resistance 2 10763768 Faim3, Fas apoptotic inhibitory molecule 10774383 Vps54, vacuolar protein sorting 54 10775519 LOC305166, similar to hypothelial protein 4933408F15 10782493 RGD1564342, similar to hypothelial protein FLJ32685 10831940 Fkbp5, FK506 binding protein 5 10849279 Sle28a2, solute carrier family 28 [sodium-coupled nucleotide transporter] 10911315 Myole, myosin 1E 10922816 Il1r2, Interleukin 1 receptor type II 10924245 Il8rb, Interleukin 8 receptor beta

BRIEF DESCRIPTION OF THE FIGURES

Some figures contain color representations or entities. Color photographs are available from the Patentee upon request or from an appropriate Patent Office. A fee may be imposed if obtained from a Patent Office.

FIGS. 1 a through j are graphical representations showing relationship between biomarker expression and sample number.

FIG. 2 is a graphical representation showing direct relationship between expression and time interval for the biomarker, myxovirus (influenza virus) resistance.

FIGS. 3 a and b are graphical representations showing the direct relationships between expression and time for myosn1E (Myole) and sialic acid binding immunoglobulin-like lectin (Siglec10).

FIGS. 4 a and b are graphical representations of RGD1564342 and Affymetrix gene is No. 10782511 at 6 hours after stroke.

FIG. 5 is a graphical representation of alpha-1-acid glycoprotein precursor expression ratios versus time. The expression ratio is the ratio between the level at a time point compared to the level at time 0 hours.

FIG. 6 is a graphical representation of alpha-2-macroglobulin precursor expression ratios versus time. The expression ratio is the ratio between the level at a time point compared to the level at time 0 hours.

DETAILED DESCRIPTION

The present disclosure teaches biomarkers, the levels or ratios of levels of which, are useful in determining a physiological time point in the evolution of a condition or event of a vascular system such as the cerebrovascular system. The determination of a physiological time line as opposed to a “clock” time line enables better stratification of patients with respect to potential therapeutic windows. The biomarkers are selected on the basis that their levels change dynamically over time following onset of a condition or event. The expression profile of the biomarkers may also change slowly over time and reach a particular profile which equates to the level of severity of symptoms. By “change” in this context includes increasing or decreasing or both over time in a statistically consistent manner. Notwithstanding, a biomarker may also be selected on the basis that its level remains relatively constant over a time period. Such a biomarker may be used as a control or in the determination of a ratio with a dynamically changing biomarker. By “dynamically changing” means an increase or decrease in levels over time. This time period may be from minutes or hours to months or years. As taught herein, the expression profile of the biomarkers correlates to a time point or period from onset of the event or condition.

Hence, the present disclosure enables a rapid, efficient and sensitive assay for the stratification of an individual with respect to the evolution of a condition or event of a vascular system such as the cerebrovascular system. It is proposed that the physiological time period will in many cases extend beyond a clock time period. Hence, patients are more accurately stratified with respect to a therapeutic window. Within any particular pre-determined time period following onset of a condition or event, the levels of the biomarkers are determined. These levels are then used to define a physiological time period which is proposed herein to be a wider period than the corresponding “clock” time period. The levels may also be represented as a ratio with another biomarker or between two different time points. Alternatively, the pre-determined time period is based on severity of symptoms. This is more applicable to chronic conditions.

Accordingly, taught herein is a method for monitoring progression of a condition or event of a vascular system such as the cerebrovascular system in a subject, the method comprising determining the levels or ratios of levels of 2 or more biomarkers, wherein the levels of the biomarkers alter during evolution of the condition or event, wherein the levels or ratios of levels of the biomarkers relative to a control determine the extent of progression of the condition or event. In an embodiment, the biomarkers listed in Table 1 have an expression profile which correlates to a time point or period since onset of the event or condition.

The term “biomarker” is used to define a gene or gene product (protein or mRNA) which is produced or released by cells following onset of a condition or event in a vascular system such as the cerebrovascular system. Terms such as “marker”, “indicator” and “instructor” may also be used to describe a biomarker. The expression profile or presence of a profile of 2 or more biomarkers correlates to a time course following onset of the condition or event. Levels of the biomarkers may be determined by levels of mRNA transcripts or levels of proteins. Hence, the present disclosure teaches the use of transcriptomics and proteomics to define the biomarker profile. By “ratio” is meant the ratio of levels of 2 different biomarkers or the ratio of levels between one biomarker and a control marker or the ratio of levels of a biomarker at 2 different time points. A control marker may be another biomarker or a non-biomarker. An example of a control is a marker which remains relatively constant over a period of time. The expression profile of biomarkers may also be based on severity of symptoms. This may be useful in determining when therapy should be initiated.

The present disclosure teaches acute and chronic conditions or events of a vascular system such as the cerebrovascular system. By “acute” is meant that the condition or event rapidly develops over from minutes to hours to days as opposed to a “chronic” condition which may take years to develop. The biomarkers for acute conditions or events are selected on the basis that their levels change dynamically during the course of development of the acute condition or event. Chronic biomarkers may be age-based or determined based on severity of symptoms. The course of development is referred to herein as the “evolution” of the condition event.

In an embodiment, the acute condition or event is stroke. This occurs in the cerebrovascular system. Hence, the present disclosure enables a method for monitoring progression of stroke in a subject, the method comprising determining the levels or ratios of levels of 2 or more biomarkers, wherein the levels of ratios of levels of the biomarkers alter during evolution of stroke, wherein the levels or ratios of levels of the biomarkers relative to a control correlate to the extent of progression of the stroke.

In another embodiment, the chronic condition or event is vascular dementia. Accordingly, the present disclosure further teaches a method for monitoring progression of vascular dementia in a subject, the method comprising determining the levels or ratios of levels of 2 or more biomarkers, wherein the levels of ratios of levels of the biomarkers alter during evolution of vascular dementia wherein the levels or ratios of levels of the biomarkers relative to a control correlate to the extent of progression of the vascular dementia.

The term “correlate” also includes “determined”.

The stage of progression of the condition or event is determined by the levels or ratios of levels of 2 or more of the biomarkers. For thrombolytic treatment of stroke, for example, an arbitrary time of 4.5 hours has been set for safe delivery of a thrombolytic agent such as tPA. It is proposed herein, that depending on the severity of the condition or event of a vascular system such as the cerebrovascular system, and also depending on the overall health of the subject, thrombolytic intervention may be indicated at a clock time point of greater than 4.5 hours. Hence, a physiological time period is determined based on the levels or ratios of levels of 2 or more biomarkers between time 0 hours and 4.5 hours following onset. As indicated above, the “ratios” may between biomarkers, a biomarker and a control marker or a biomarker at different time points. It is proposed that thrombolytic treatment can be safely provided while the physiological time line remains within parameters determined for the equivalent clock time. The corresponding physiological time period for stroke is proposed herein to be approximately from about 0 hours to 10 hours such as 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 or 10 hours. Similarly, a subject may present less than 4.5 hours post onset of stroke but with a biomarker expression profile instructive as to greater than 4.5 hours. Such a subject may then not be deemed eligible for tPA treatment.

For treatment of other conditions such as vascular dementia, the expression profile of the biomarkers may be determined in a control subject having a certain level of severity of symptoms. The levels or ratios of levels of biomarkers then equate to that level of severity of symptoms. A subject with such an expression profile of biomarkers may then require therapeutic intervention.

Hence, enabled herein is a method for monitoring progression of a thromboembolic condition or event of a vascular system such as the cerebrovascular system in a subject, the method comprising determining the levels or ratios or levels of 2 or more biomarkers, the biomarkers selected on the basis that in the time period since onset of the thromboembolic condition or event, the levels or ratios of levels of the biomarkers are instructive as to a time point along a time line, wherein the levels or ratios of the levels of the biomarkers relative to a control correlate to the extent of progression of the condition or event.

Another aspect taught herein is a method for monitoring progression of a chronic condition or event of a vascular system such as the cerebrovascular system in a subject, the method comprising determining the levels or ratios or levels of 2 or more biomarkers, the biomarkers selected on the basis that a particular profile is obtained which equates to the severity of symptoms of the condition or event, wherein the levels or ratios of the levels of the biomarkers relative to a control correlate to the extent of progression of the condition or event.

Aspects taught herein are predicated in part on the determination that the ischemia or hemorrhage within a vascular system such as the cerebrovascular system triggers a rapid and stereotyped acute phase response which is used to establish biological time points since onset of the ischemic or hemorrhagic condition or event. Cell death, for example, releases cell contents into the blood stream. It is taught herein to replace the clock time points with a physiological time line based on the profile of levels of selected biomarkers. Although this is particularly applicable to ischemic conditions or events of a vascular system such as the cerebrovascular system, it also applies to hemorrhagic conditions or events.

Another aspect enabled herein is a method for stratifying a subject with respect to progression of a condition or event of a vascular system such as the cerebrovascular system, the method comprising determining the levels or ratios of levels of 2 or more biomarkers, the levels or ratios of levels of which alter over time from onset of the condition or event wherein the combination of the 2 or more levels or ratios of levels establishes a physiological time line which, when compared to a control, enables identification of the extent of progression of the condition or event. The physiological time line may also equate to severity of symptoms.

The extent of progression is important in order to define certain therapeutic windows. For ischemic conditions involving an occlusion, administration of a thrombolytic agent is recommended within a 4.5 hour time period since onset. However, the exact time point of onset may not be known with any accuracy. Hence, the levels or ratios of levels of biomarkers or the biomarker profile is used to determine physiologically the likely time period since onset. For chronic conditions, the biomarker expression profile can be used to determine when a subject should receive treatment or when the treatment regime should change.

By “condition” or event of a vascular system such as the cerebrovascular system” is meant any disease or physiological phenomenon arising from an ischemic incident or hemorrhage in a vascular system. Examples of such conditions and events include stroke, myocardial ischemia and infarction and cardiomyopathies including ischemic cardiomyopathy and ischemic heart disease as well as vascular dementia. In an embodiment, the condition or event occurs in the cerebrovascular system such as ischemic or hemorrhagic stroke. In an embodiment, the condition or event is ischemic stroke since it is critical to know the period of progression of the stroke to establish whether the patient is still within the therapeutic window for thrombolytic intervention. In another embodiment, the condition is vascular dementia which may take many years to develop. However, it is also critical to assist clinicians in determining when therapy needs to be initiated or altered.

In an embodiment, the condition or event of a vascular system such as the cerebrovascular system is of ischemic origin wherein thrombolytic intervention has the potential to alleviate the occlusion which led to the ischemic event. The present disclosure further teaches using the profile of expression of the biomarkers to distinguish between conditions and events such as between ischemic and hemorrhagic stroke. Hence, the profile of biomarkers may change depending on the condition or event.

“Stratification” includes identification, diagnosis, prognosis, clarification, monitoring and/or determination of the presence, level, severity, state and/or classification of an acute condition or event of a vascular system such as the cerebrovascular system. In an embodiment, the subject is stratified with respect to progression of the acute condition or event from onset. Generally, this is based on comparing a knowledge base of levels or ratios of levels of biomarkers in body fluid including plasma, whole blood and serum to another knowledge base of pre-determined levels, statistically correlated to the evolution of the condition or event. The correlation may be based on a pre-determined time period or on a pre-determined level of severity of symptoms.

Hence, the present disclosure teaches the identification of a correlation between the levels or ratios of levels of particular biomarkers and evolution of the condition or event since onset. In an embodiment, the levels of biomarkers are determined at clock time points such as at but not limited to between 0 hours and 4.5 hours following onset of the condition or event. This information becomes a control knowledge base of data. Determination of the levels of the biomarkers by a patient provides a test knowledge base of data. Comparison of the test knowledge base with the control knowledge base enables an estimate of the likely point in the evolution of the condition or event. In another embodiment, the biomarker expression profile is correlated to severity of symptoms.

As indicated above, a condition or event of a vascular system such as the cerebrovascular system includes stroke (ischemic or hemorrhagic stroke) and cardiovascular disease such as ischemic mitochondrial infarction, and organ damage due to ischemic conditions. Those conditions are regarded as being acute. In a particular embodiment, the condition or event is ischemic stroke. The term “ischemic stroke” as used herein is to be considered as an individual condition as well as a spectrum of conditions including a range of risk indicators of the level of disease progression. This risk ranges from minor to extreme. The ability to monitor and identify markers of stroke enables decisions on which type of medical intervention is required from behavioural modification and medicaments to surgical intervention. This is particularly the case for monitoring the window of thrombolytic intervention. The physiological time line is proposed herein to define a therapeutic window for thrombolytic intervention which is wider than the clock time window of 4.5 hours.

The present disclosure teaches any or all conditions within the clinical spectrum of “ischemic stroke” such as pre-stroke and ischemic attacks.

In another embodiment, the condition or event is vascular dementia, Alzheimer's disease, Parkinson's disease or other conditions resulting in dementia. Such conditions are regarded as chronic. The physiological time line then matches severity of symptoms or may be age-based.

Reference herein to a “subject” includes a human which may also be considered an individual, patient, host, recipient or target. The subject may also be an animal, such as used in an animal model.

Useful biomarkers contemplated for use herein include 2 or more biomarkers selected from those listed in Table 1. In an embodiment, the biomarkers include 2 or more of the biomarkers listed in Table 2. Tables 1 and 2 list biomarkers useful in the practice of the present disclosure by Affymetrix gene identifier (ID) number (Affymetrix gene identifier). Information on the genes can be obtained from the Affymetrix website [NetAffx (Trademark)] which can be accessed at http://www.affymetrix.com/analvsis/index.affx. Where available, an ENSEMBL identifier is also provided which can be accessed through the ENSEMBL rat genome website at http://www.ensembl.org/Rattus_norvegicus. Where a gene is identified as a “rat gene”, the present disclosure extends to a mammalian homolog thereof and in particular a human homolog. The human homolog may be referred to by a different name. The term “biomarker” extends to both the gene or gene product such as a protein or mRNA transcript.

By name, particularly useful biomarkers include alpha-1-macroglobulin precursor, alpha-2-macroglobulin precursor, CINC-1, myxovirus (influenza virus) resistance 2, nuclear receptor MrgA10 RF-amide G protein-coupled receptor, lactate dehydrogenase C, FK506 binding protein 5, interleukin 1 receptor type II, interleukin 8 receptor beta formyl peptide receptor 1, paired-immunoglobulin-like receptor 8, myeloid cell surface antigen CD33 precursor (Siglec), lute carrier family 28 (sodium-coupled nucleoside transporter) and vacuolar protein sialic acid binding immunoglobulin-like lectin 10.

In an embodiment, the levels or ratios of levels of between about 2 and about 2054 biomarkers are determined from Table 1. In an embodiment, the biomarkers may be reviewed as sub-groups of from 2 to 500 or 2 to 100 or 2 to 50 biomarkers. In an embodiment, the levels or ratios of levels of from about 2 to 20 biomarkers are determined including about 8 to 15 biomarkers such as about 12 biomarkers. Selection of groups of biomarkers may be made based on patient data and/or the condition or event being diagnosed or treated. In an embodiment, for about 2 to about 25 biomarkers are selected from the list set forth in Table 2, including from about 8 to 15 such as 12 biomarkers.

The biomarker profile determined may also be selected based on the age, weight, sex, overall physical wellbeing or other parameters of the subject such as severity of symptoms. Hence, a profile of biomarkers may be selected in a personal medicine approach to establish the physiological time line of the condition or event.

The present disclosure enables, therefore, a physiological time line to be determined for a subject based on biomarker profile which in turn is instructive as to which therapeutic intervention protocol is the most appropriate. The stratification or profiling enables early diagnosis, confirmation of a clinical diagnosis, treatment monitoring and treatment selection as well as determining whether a subject is within a therapeutic window for thrombolytic or other treatment treatment.

Another aspect taught herein is an assay to identify whether a subject can be given thrombolytic intervention following onset of an ischemic condition or event in a vascular system such as the cerebrovascular system, the method comprising determining levels or ratios of levels of 2 or more biomarkers which correlate with evolution of the condition or event following onset at time 0 hours and 4.5 hours wherein a comparison of the biomarker levels or ratios of levels with a control enable determination of whether the subject is within the thrombolytic intervention therapeutic window.

The disclosure enables a method of treating a subject who has or is suspected of having suffered an acute ischemic condition or event of a vascular system such as the cerebrovascular system, the method comprising determining the levels or ratios of levels of 2 or more biomarkers, wherein the levels or ratios of levels of the biomarkers alter during evolution of the condition or event, wherein the levels or ratios of levels of the biomarkers relative to a control determine the extent of progression of the condition or event and where the levels of the biomarkers approximately equate to the levels present from 0 hours to 4.5 hours after onset of the condition or event and administering to the subject a thrombolytic agent. If the levels or ratios of levels of the biomarkers indicate that physiologically the subject is within the 0 to 4.5 hour time period from onset.

The present disclosure is instructional for a method of treating a subject who has or is suspected of having suffered a stroke the method comprising determining the levels or ratios of levels of 2 or more biomarkers, wherein the levels or ratios of levels of the biomarkers alter during evolution of the stroke, wherein the levels or ratios of levels of the biomarkers relative to a control determine the extent of progression of the stroke and where the levels or ratios of levels of the biomarkers approximately equate to the levels present from 0 hours to 4.5 hours after onset of the stroke, administering to the subject a thrombolytic agent. If the levels or ratios of levels of the biomarkers indicate that physiologically the subject is within the 0 to 4.5 hour time period from onset.

Yet another aspect taught herein is a method of treating a subject the method comprising determining the levels or ratios of levels of 2 or more biomarkers, wherein the levels or ratios of levels of the biomarkers alter during evolution of a condition or event wherein the levels or ratios of levels of the biomarkers equates to a level of severity of symptoms, wherein the levels or ratios of levels of the biomarkers relative to a control determine the extent of progression of the condition or event and then providing treatment to the subject when the levels or ratios of levels equate to a set severity of symptoms.

The physiological time period corresponding to the levels or ratios of levels of the biomarkers pre-determined between 0 and 4.5 hours is wider than the clock time period. Hence, more patients will qualify for thrombolytic treatment. Notwithstanding, the present disclosure teaches the identification of patients having a biomarker expression profile of >4.5 hours post onset who would be contraindicated for thrombolytic treatment.

Yet another aspect enabled herein is the use of 2 or more biomarkers, the levels of which dynamically alter during evolution of an acute condition or event of a vascular system such as the cerebrovascular system in a subject, in the manufacture of a diagnostic assay to determine the extent of progression of the condition or event.

As indicated above, the 2 or more biomarkers are generally selected from the list in Table 1. In an embodiment, the 2 or more biomarkers are selected from the list in Table 2.

Provided herein, therefore, is a panel of biomarkers, expression of which corresponds to the extent of progression of a condition or event of a vascular system such as the cerebrovascular system.

In an embodiment, temporal changes in biomarkers following ischemic or hemorrhagic stroke are as follows:

Steady decline with time of onset 10750524 (Mx2, myxovirus (influenza virus) resistance 2) Steady increase to 6 hours from onset then falling 10940615 10926252

CINC-1

Rapid early rise then rapid fall by 6 hours from onset 10722208 (Mrga 10, nuclear receptor Mrga10 RF-amide G protein-coupled receptor) 10707142 (Ldhc, lactate dehydrogenase C) 10831940 (Fkbp5, FK506 binding protein 5) 10828832 Rapid early rise then persistent high expression to 6 hours from onset followed by slow fall by 24 hours 10922816 (Il1r2, Interleukin 1 receptor, type II) 10924245 (Il8rb, Interleukin 8 receptor, beta) 10718351 (Fpr1; formyl peptide receptor 1) 10854847 10703666 (Pirb, paired-Ig-like receptor B) 10721261 (LOC687856, similar to myeloid cell surface antigen CD33 precursor) Steady rise to 6 hours, normalised by 24 hours from onset 10775519 (LOC305166, similar to hypothetical protein 4933408F15) 10849279 (Slc28a2, Solute carrier family 28 (sodium-coupled nucleoside transporter)) 10774383 (Vps54, Vacuolar protein sorting 54 [yeast]) 10754363 10751434 Rapid fall by 1 hour, persistent suppression to 6 hours, then normalising by 24 hours from onset 10763768 (Faim3, Fas apoptotic inhibitory molecule) 10748273 (Cd79b, CD79B antigen) 10769765 10911315 (Myo1e, myosin 1E) 10706308 (Siglec10 sialic acid binding Ig-like lectin 10) No change of expression to 3 hours then increase by 6 hours from onset 10782493 (RGD1564342, similar to hypothetical protein FLJ32685) 10782511 Alpha-1-acid glycoprotein precursor No change of expression to 6 hours then increase by 24 hours from onset Alpha-2-macroglobulin precursor

There are many methods which may be used to detect the levels of the biomarkers including determination of mRNA expression levels and/or protein levels such as by immunological means or by mass spectrometry including liquid chromatography and electrospray ionization-tandem mass spectrometry.

Immunological assays for the biomarkers may be in any convenient format as known in the art. These include Western blots, immunohistochemical assays and ELISA assays. Any means for detecting a level of a biomarker of the expression or protein level can be used in accordance with the present disclosure. Any one of a range of genetic assays may be conducted to quantitative mRNA levels and expression level including quantitative PCR. In an embodiment, microarrays of genetic molecules or immunological agents such as antibodies specific for biomarkers are employed. In one aspect, a solid phase support is provided comprising ligands which are capable of capturing the biomarkers. The solid phase support may be in the form of a chip, microarray, dipstick, micro- or nano-titer plate with wells and the like. The solid phase microarray may measure levels or changes in expression levels, velocities, concentrations or activities of the biomarkers to thereby provide a profile of biomarker expression. The ligands include antibodies, nucleic acid probes, receptors or other molecule capable of capturing a biomarker. The solid phase array may also be interfaced with a computer to assist in the analysis and/or generation of data. In an embodiment, the levels or ratios of levels of the biomarkers are subjected to multivariate analysis in a multivariate statistical model.

The biological sample is any fluid or cell or tissue extract in a subject which comprises the biomarker. In another embodiment, the biological sample includes serum, whole blood or blood plasma, lymph, urine, saliva or a cell extract. Generally, samples are analyzed at point of care facilities or analyzed remote from the point of care facility but report to the facility such as by a web-based reporting system.

In an embodiment, the present disclosure teaches identification of the presence of biomarkers associated with the evolution of an ischemic condition or event within a vascular system such as the cerebrovascular system which is instructive as to whether a subject is eligible for thrombolytic intervention. In order to detect the levels of the biomarkers, a biological sample is prepared and analyzed for a difference in levels or ratios of levels between the subject being tested and a control. In this context, a “control” includes the levels in a statistically significant comparable population free of a condition or event or following the condition or event. Conveniently, the control is a knowledge database which comprises statistically validated levels or ratios of levels of the biomarkers at pre-determined the points such as between time 0 hours and the 4.5 hours following onset of the condition or event. The time points may be taken at any time between the 0 hour to 4.5 hour range such as at 0, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, 210 minutes, 240 minutes and 270 minutes, or at any points inbetween. Alternatively, the control is based on severity of symptoms in a control subject. At various stages during progression of a condition or event, a biomarker expression profile is determined.

The identification of the association between the pathophysiology of a condition or event of a vascular system such as the cerebrovascular system and levels of, or ratios of, biomarkers permits the early screening of individuals to identify those who may benefit from thrombolytic intervention or other form of therapy. The subject assay enables practitioners to identify or stratify individuals who are within the therapeutic window for thrombolytic intervention based on physiological means rather than just “clock time” and who may benefit from this treatment. This treatment may also be complemented with certain behavioral or therapeutic or dietary protocols to reduce the risk of further exacerbating vascular disease. Furthermore, for more chronic conditions, the biomarker expression profile can assist a clinician to decide when therapy should be initiated or changed.

Even yet another aspect of the present disclosure teaches a method of treatment of a subject comprising assaying the subject with respect to the levels or ratios of levels of 2 or more biomarkers which levels or ratios of levels define the evolution of a condition or event of a vascular system such as the cerebrovascular system wherein the levels or ratios of levels of the biomarkers relative to a control provides a correlation to the presence, state, classification or progression of the condition or event and then providing therapeutic intervention to the subject based on the progression of the condition or event.

In an embodiment, the present disclosure enables a method of treatment of a subject comprising assaying the subject with respect to the levels or ratios of levels of 2 or more biomarkers which define the evolution of a stroke wherein the levels or ratios of levels of the biomarkers relative to a control provide a correlation to the presence, state, classification or progression of the stroke and then providing therapeutic intervention to the subject based on the progression of the stroke.

Enabled herein is a method for the treatment of a neurological condition such as a stroke or symptoms of stroke by determining the extent of progression of an acute condition or event of the cerebrovascular system leading to the neurological condition and providing therapeutic intervention based on the extent of progression. Examples of therapeutic intervention include administration of a thrombolytic agent, oral aspirin, surgical intervention and/or behavoral and/or care intervention.

A web-based system is provided herein where data on expression levels of biomarkers associated with the evolution of a condition or event of a vascular system such as the cerebrovascular system are provided by a client server to a central processor which analyzes and compares to a control and optionally considers other information such as patient age, sex, weight and other medical conditions and then provides a report, such as, for example, a risk factor for disease severity or progression or status or an index of probability that the condition or event is at a certain stage or time from onset. The report is conveniently provided to a clinician at a point of care facility.

Hence, knowledge-based computer software and hardware are also taught by the present disclosure.

In an embodiment, the assay enabled herein may be used in existing or newly developed knowledge-based architecture or platforms associated with pathology services. For example, results from the assays are transmitted via a communications network (e.g. the internet) to a processing system which generates a physiological time period, based on pre-determined data, which is then forwarded to an end user in the form of a diagnostic or predictive report. In an embodiment, for example, the report specifies whether the patient is within a particular the therapeutic window. One such therapeutic window is the time period for thrombolytic intervention such as in the case of ischemic stroke.

The assay may, therefore, be in the form of a kit or computer-based system which comprises the reagents necessary to detect the concentration of the biomarkers directly or via expression of genes and the computer hardware and/or software to facilitate determination and transmission of reports to a clinician at a point of care facility.

A method is taught herein of allowing a user to determine the status of a subject with respect to an acute condition or event of a vascular system such as the cerebrovascular system, the method including receiving data, in the form of levels or ratios of levels of 2 or more biomarkers associated with the evolution of the condition or event; wherein the levels or ratios of levels of the biomarker relative to a control provide a correlation to the presence, state, classification or progression of the condition or event, from the user via a communications network which processes the data and which determines the status of the subject in accordance with a comparison with pre-determined values, wherein the results indicating the status of the subject are transferred to the user via the communications network. The “status” is generally the predicted time point following onset. The 2 or more biomarkers are selected from those listed in Table 1 or Table 2.

Conveniently, the method generally further includes having the user determine the data using a remote end station, and transferring the data from the end station to the base station via the communications network.

The base station can include first and second processing systems, in which case the method can include transferring the data to the first processing system, transferring the data to the second processing system, and causing the first processing system to perform the processing to generate the an estimate of the time since onset.

The second processing system may also be coupled to a database adapted to store pre-determined data which queries the database to obtain at least selected pre-determined data from the database and compares the selected pre-determined data to the subject data or generating a predicted probability index that the condition or event as progressed to a certain extent.

The present disclosure also teaches a base station for determining the status of a subject with respect to an estimated physiological time period since onset, the base station including:

(a) a data storage facility;

(b) a data processing system, the processing system being adapted to receive subject data from a user via a communications network, the data including levels or ratios of levels of biomarkers associated with the evolution of a condition or event of a vascular system such as the cerebrovascular system, comparing the data to pre-determined data and determining the status of the subject in accordance with the results of the processing including the comparison; and

(c) an output function to provide an indication of the status of the subject to the user via the communications network.

In an embodiment, an algorithm is used to compare test data with pre-determined data. The algorithm may perform univariate or multivariate statistical analysis.

The processing system can be adapted to receive data from a remote end station adapted to determine the data.

In accordance with this embodiment, levels or ratios of levels of the biomarkers may be screened alone or in combination with other biomarkers of a condition or event. An “altered” level means an increase or elevation or a decrease or reduction in the concentrations of the biomarkers or their velocities or level of expression of a gene. It is proposed herein that the levels or ratios of levels of the biomarkers are indicative of extent of progressive or evolution of condition or the event.

The determination of the concentrations or levels or velocities or ratios of levels of the biomarkers enable establishment of a diagnostic rule based on the concentrations, levels, velocities or ratios relative to controls. Alternatively, the diagnostic rule is based on the application of a statistical and machine learning algorithm. Such an algorithm uses relationships between levels or ratios of levels biomarkers and disease status observed in training data (with known disease status) to infer relationships which are then used to predict the status of patients with unknown status. An algorithm is employed which provides an index of probability that a patient has had a condition or event within a certain time period. The algorithm would perform in an embodiment, a univariate or multivariate analysis function. In a particular embodiment, the training data comprise the levels or ratios of levels of the biomarkers within a pre-determined time period. In an embodiment, this time period is from about 0 hours to about 4.5 hours. Thereafter, the time period is estimated based on a physiological time period which is proposed to be longer than the clock time period of, for example, 0 to 4.5 hours. Hence, more patients will likely qualify for a particular treatment associated with this physiological time period.

Hence, a diagnostic rule is enabled herein based on the application of statistical and machine learning algorithms. Such an algorithm uses the relationships between levels or ratios of levels of biomarkers and in training data to infer relationships which are then used to predict the time period in patients with unknown status. Practitioners skilled in the art of data analysis recognize that many different forms of inferring relationships in the training data may be used without materially changing the present disclosure.

Hence, the present disclosure is instructional on the use of a knowledge base of training data comprising levels or ratios of levels of biomarkers associated with the evolution of an acute condition or event of a vascular system such as the cerebrovascular system in a subject over a clock time period to generate an algorithm which, upon input of a second knowledge base of data comprising levels of the biomarkers from a patient with an unknown status of time of onset, provides an index of probability that predicts the likely time period since onset. Alternatively, the training data comprise a biomarker expression profile based on level of severity of symptoms. Hence, the algorithm then provides an index of probability that a patient has reached a certain stage of disease progression. This information is then useful to determine windows for appropriate therapeutic intervention.

The term “training data” includes knowledge of levels or ratios of the biomarkers factors relative to a control. A “control” includes a comparison to levels of the biomarkers in a subject with known onset time of the condition or event.

Hence, the “training data” includes levels or ratios of 2 or more biomarkers.

Data generated from the levels of the biomarkers are input data. The input of data comprising the levels of the biomarkers are compared with a control or is put into the algorithm which provides a risk value of the likelihood that the subject being in a defined therapeutic window or time period. A treatment regime is then selected such as based on whether the subject is eligible for thrombolytic intervention, aspirin, management or surgical intervention.

In an embodiment, a method is enabled for monitoring the progression of a condition or event of a vascular system such as the cerebrovascular system in a patient, comprising:

(a) providing a sample from a patient;

(b) determining the levels or ratios or levels of 2 or more biomarkers wherein the levels or ratios of the biomarkers relative to a control provide a correlation to the presence, state, classification or progression of the condition or event;

(c) repeating steps (a) and (b) at a later point in time and comparing the result of step (b) with the result of step (c) wherein a difference in the index of probability is indicative of the progression of the condition in the patient. In an embodiment, the condition or event is a stroke.

Reference to an “algorithm” or “algorithmic functions” as outlined above includes the performance of a univariate or multivariate analysis function. This includes the determination of an F-statistic or a p-value associated with an F-statistic. A range of different architectures and platforms may be implemented in addition to those described above. It will be appreciated that any form of architecture suitable for implementing the present disclosure may be used. However, one beneficial technique is the use of distributed architectures. In an embodiment, a number of end stations may be provided at respective geographical locations. This can increase the efficiency of the system by reducing data bandwidth costs and requirements, as well as ensuring that if one base station becomes congested or a fault occurs, other end stations could take over. This also allows load sharing or the like, to ensure access to the system is available at all times.

In this case, it would be necessary to ensure that the base station contains the same information and signature such that different end stations can be used.

It will also be appreciated that in one example, the end stations can be hand-held devices, such as PDAs, mobile phones, or the like, which are capable of transferring the subject data to the base station via a communications network such as the Internet, and receiving the reports. Hence, point of care facilities can be remote from where the levels of the biomarkers are determined.

In the above aspects, “data” mean the levels, ratios of levels, concentrations, velocities or level of transcription of the biomarkers. The “communications network” includes the internet. When a server is used, it is generally a client server or more particularly a simple object application protocol (SOAP).

A report outlining the likelihood of time of onset of the condition or event is then issued.

The present disclosure further teaches the use of the levels of ratios or levels of 2 or more biomarkers listed in Table 1 or Table 2 to determine the extent of progression of a condition or event of a vascular system such as the cerebrovascular system.

Aspects of the present disclosure are described by the following non-limiting Examples.

Example 1 Identification of Biomarkers

Biomarkers are identified by expression analysis versus selected time points after onset of a stroke in a rat stroke model. mRNA was extracted from whole blood of rats which had an induced stroke. mRNA was measured using Affymetrix (Trademark) rat gene expression arrays of type RaGene-1-O-st-v1. The data were statistically analyzed using linear models such as those implemented in the LIMMA package (Smyth et al. (2005) LIMMA:Linear Models for microarray data In Bioinformatics and Computational Biology Solutions using R and Bioconductor R. Gentleman V Carey, S. Dudoit, R Irizarry W Huber (Eds), Springer, New York: 397-420) The list of biomarkers is provided in Table 1.

In an embodiment, the biomarkers are listed in Table 2. The present disclosure extends to multiple subsets of biomarkers from Table 1 or Table 2 based on patient data (disease history, sex, weight, age, etc) or on the condition or event being diagnosed or treated.

The biomarkers in Tables 1 and 2 are listed by Affymetrix gene identifier (ID) number (Affymetrix gene identifier). The biomarkers were selected with a p-value cutoff over all time points of 5×10⁻⁶. Generally, 6 time points were used at which to measure the levels of the biomarkers. The order of the genes is by p-value of the F-statistic from decreasing order of significance. Information on the genes can be obtained from the Affymetrix website [NetAffx (Trademark)] which can be accessed at http://www.affymetrix.com/analysis/index.affx. Where available, an ENSEMBL identifier is also provided which can be accessed through the ENSEMBL rat genome website at http://www.ensembl.org/Rattus_norvegicus. The term “NA” is used when the ENSEMBL identifier is not available. Where a gene is identified as a “rat gene”, the present disclosure extends to a mammalian homolog thereof and in particular a human homolog. The human homolog may be referred to by a different name.

Example 2 Expression of Biomarkers

Expression studies of the biomarkers are provided graphically in FIGS. 1 through 6. The levels of biomarkers are conveniently subjected to multivariate statistical analysis. The biomarkers are referred to by Affymetrix gene identifier number. In summary, a list of biomarkers based on expression profile is provided below:

Steady decline with time of onset 10750524 (Mx2, myxovirus (influenza virus) resistance 2) Steady increase to 6 hours from onset then falling 10940615 10926252

CINC-1

Rapid early rise then rapid fall by 6 hours from onset 10722208 (Mrga10, nuclear receptor Mrga10 RF-amide G protein-coupled receptor) 10707142 (Ldhc, lactate dehydrogenase C) 10831940 (Fkbp5, FK506 binding protein 5) 10828832 Rapid early rise then persistent high expression to 6 hours from onset followed by slow fall by 24 hours 10922816 (Il1r2, Interleukin 1 receptor, type II) 10924245 (Il8rb, Interleukin 8 receptor, beta) 10718351 (Fpr1; formyl peptide receptor 1) 10854847 10703666 (Pirb, paired-Ig-like receptor B) 10721261 (LOC687856, similar to myeloid cell surface antigen CD33 precursor) Steady rise to 6 hours, normalised by 24 hours from onset 10775519 (LOC305166, similar to hypothetical protein 4933408F15) 10849279 (Slc28a2, Solute carrier family 28 (sodium-coupled nucleoside transporter)) 10774383 (Vps54, Vacuolar protein sorting 54 [yeast]) 10754363 10751434 Rapid fall by 1 hour, persistent suppression to 6 hours, then normalising by 24 hours from onset 10763768 (Faim3, Fas apoptotic inhibitory molecule) 10748273 (Cd79b, CD79B antigen) 10769765 10911315 (Myo1e, myosin 1E) 10706308 (Siglec10 sialic acid binding Ig-like lectin 10) No change of expression to 3 hours then increase by 6 hours from onset 10782493 (RGD1564342, similar to hypothetical protein FLJ32685) 10782511 Alpha-1-acid glycoprotein precursor No change of expression to 6 hours then increase by 24 hours from onset Alpha-2-macroglobulin precursor

Those skilled in the art will appreciate that aspects of aspects described herein are susceptible to variations and modifications other than those specifically described. It is to be understood that these aspects include all such variations and modifications. These aspects also include all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of the steps or features.

BIBLIOGRAPHY

-   Donnan et al. (2008) Lancet 371:1612-1623 -   Hacke et al. (2004) Lancet 363:768-774 -   Hacke et al. (2008) N Engl J Med 359:1317-1329 -   Lees et al. (2010) Lancet 375:1695-1703 -   Smyth et al. (2005) LIMMA:Linear Models for microarray data In     Bioinformatics and Computational Biology Solutions using R and     Bioconductor R. Gentleman V Carey, S. Dudoit, R Irizarry W Huber     (Eds), Springer, New York: 397-420 -   Strong et al. (2007) Lancet Neurol 6:182-187 

1-29. (canceled)
 30. A method for monitoring progression of a condition or event of a vascular system in a subject, said method comprising determining the levels or ratios of levels of 2 or more biomarkers selected from the list set forth in Table 1, wherein the levels or ratios of levels of the biomarkers alter during evolution of the condition or event, wherein the levels or ratios of levels of the biomarkers relative to a control correlate to the extent of progression of the condition or event.
 31. The method of claim 30, wherein the vascular system is the cerebrovascular system.
 32. The method of claim 30, wherein the condition or event is an ischemic condition or event.
 33. The method of claim 30, wherein the condition or event is selected from ischemic stroke, ischemic myocardial infarction and vascular dementia.
 34. The method of claim 31, wherein the condition or event is hemorrhagic stroke.
 35. The method of claim 30, wherein the 2 or more biomarkers are selected from the biomarkers listed in Table
 2. 36. The method of claim 33, wherein the correlation between onset of a stroke and progression is determined by measuring changes in expression levels of 2 or more of the following genes listed by Affymetrix ID number: Steady decline with time of onset 10750524 Steady increase to 6 hours from onset then falling 10940615 10926252 Rapid early rise then rapid fall by 6 hours from onset 10722208 10707142 10831940 10828832 Rapid early rise then persistent high expression to 6 hours from onset followed by slow fall by 24 hours 10922816 10924245 10718351 10854847 10703666 10721261 Steady rise to 6 hours, normalised by 24 hours from onset 10775519 10849279 10774383 10754363 10751434 Rapid fall by 1 hour, persistent suppression to 6 hours, then normalising by 24 hours from onset 10763768 10748273 10769765 10911315 10706308 No change of expression to 3 hours then increase by 6 hours from onset 10782493
 10782511. 37. The method of claim 30, wherein the subject is human.
 38. The method of claim 37, wherein the method allows stratification of a human subject on the basis of whether or not the subject is within a therapeutic window to receive a particular treatment.
 39. The method of claim 38, wherein the treatment is thrombolytic intervention.
 40. The method of claim 39, wherein the therapeutic window to receive thrombolytic treatment is defined by levels or ratios of levels of the biomarkers being approximately the same as the levels at from 0 hours to 4.5 hours after onset of the condition or event.
 41. A method of treating a subject having or suspected of having suffered an acute ischemic condition or event of a vascular system, said method comprising: determining the levels or ratios of levels of 2 or more biomarkers selected from the list set forth in Table 1, wherein the levels or ratios of levels of the biomarkers alter during evolution of the condition or event, wherein the levels or ratios of levels of the biomarkers relative to a control correlate to the extent of progression of the condition or event and wherein the levels or ratios of levels of the biomarkers approximately equate to the levels or ratios of levels present from between 0 hours to 4.5 hours after onset of the condition or event; and, administering to the subject a thrombolytic agent if the levels or ratios of levels of the biomarkers indicate that physiologically the subject is within the 0 to 4.5 hour time period from onset.
 42. A method of treating a subject having or suspected of having suffered a condition or event of a vascular system, said method comprising: determining the levels or ratios of levels of 2 or more biomarkers selected from the list set forth in Table 2, wherein the levels or ratios of levels of the biomarkers alter during evolution of the condition or event, wherein the levels or ratios of levels of the biomarkers relative to a control correlate to the extent of progression of the condition or event and wherein the levels or ratios of levels of the biomarkers approximately equate to the levels or ratios of levels present from between 0 hours to 4.5 hours after onset of the condition or event; and, administering to the subject a thrombolytic agent if the levels or ratios of levels of the biomarkers indicate that physiologically the subject is within the 0 to 4.5 hour time period from onset.
 43. The method of claim 41, wherein the vascular system is the cerebrovascular system.
 44. The method of claim 41, wherein the condition or event is selected from ischemic stroke, ischemic myocardial infarction, and vascular dementia.
 45. The method of claim 43, wherein the condition or event is a hemorrhagic stroke.
 46. The method of claim 44, wherein the correlation between onset of a stroke and progression is determined by measuring changes in expression levels of 2 or more of the following genes listed by Affymetrix ID number: Steady decline with time of onset 10750524 Steady increase to 6 hours from onset then falling 10940615 10926252 Rapid early rise then rapid fall by 6 hours from onset 10722208 10707142 10831940 10828832 Rapid early rise then persistent high expression to 6 hours from onset followed by slow fall by 24 hours 10922816 10924245 10718351 10854847 10703666 10721261 Steady rise to 6 hours, normalised by 24 hours from onset 10775519 10849279 10774383 10754363 10751434 Rapid fall by 1 hour, persistent suppression to 6 hours, then normalising by 24 hours from onset 10763768 10748273 10769765 10911315 10706308 No change of expression to 3 hours then increase by 6 hours from onset 10782493
 10782511. 47. The method of claim 48, wherein from 2 to about 20 biomarkers are selected.
 48. A diagnostic assay for determining an extent of progression of a condition or event of a vascular system in a subject comprising two or more biomarkers selected from Table
 1. 49. The diagnostic assay of claim 48, wherein the vascular system is the cerebrovascular system.
 50. The diagnostic assay of claim 48, wherein the condition or event is an ischemic condition or event.
 51. The diagnostic assay of claim 48, wherein the condition or event is selected from an ischemic stroke, ischemic myocardial infarction, hemorrhagic stroke and vascular dementia.
 52. The diagnostic assay of claim 48, wherein the two or more biomarkers are selected from the biomarkers listed in Table
 2. 53. A method of allowing a user to determine the status of a subject with respect to an acute condition or event of a vascular system such as the cerebrovascular system, said method comprising the user receiving data, in the form of levels or ratios of levels of 2 or more biomarkers selected from Table 1 which correlate with the evolution of the condition or event; wherein the levels or ratios of levels of the biomarker relative to a control provide a correlation to the presence, state, classification or progression of the condition or event, from the user via a communications network which processes the data and which determines the status of the subject in accordance with a comparison with pre-determined values, wherein the results indicating the status of the subject are transferred to the user via the communications network. 